Homeostatic Plasticity Mediated by Rod-Cone Gap Junction Coupling in Retinal Degenerative Dystrophic RCS Rats

Abstract

Rod-cone gap junctions open at night to allow rod signals to pass to cones and activate the cone-bipolar pathway. This enhances the ability to detect large, dim objects at night. This electrical synaptic switch is governed by the circadian clock and represents a novel form of homeostatic plasticity that regulates retinal excitability according to network activity. We used tracer labeling and ERG recording in the retinae of control and retinal degenerative dystrophic RCS rats. We found that in the control animals, rod-cone gap junction coupling was regulated by the circadian clock via the modulation of the phosphorylation of the melatonin synthetic enzyme arylalkylamine N-acetyltransferase (AANAT). However, in dystrophic RCS rats, AANAT was constitutively phosphorylated, causing rod-cone gap junctions to remain open. A further b/a-wave ratio analysis revealed that dystrophic RCS rats had stronger synaptic strength between photoreceptors and bipolar cells, possibly because rod-cone gap junctions remained open. This was despite the fact that a decrease was observed in the amplitude of both a- and b-waves as a result of the progressive loss of rods during early degenerative stages. These results suggest that electric synaptic strength is increased during the day to allow cone signals to pass to the remaining rods and to be propagated to rod bipolar cells, thereby partially compensating for the weak visual input caused by the loss of rods.

Evaluation of visual function in Royal College of Surgeon rats using a depth perception visual cliff test

“…The latency to dismount the stage strongly correlated with ONL thickness and with the number of M- and S-cones, suggesting that this visual function test may be used to assess photoreceptor degeneration. The morphological data presented are in accordance with previous studies by our group (Tzameret et al, 2014, 2015) and by others (Girman et al, 2005; Hou et al, 2017; Huang et al, 2011; Matthes & LaVail, 1989). However, to the best of our knowledge, this is the first study that examined the degeneration of different cone types over a time frame of 15 weeks.…”

The urokinase‐type plasminogen activator system as drug target in retinitis pigmentosa: New pre‐clinical evidence in the rd10 mouse model

“…On the other hand, improvement of scotopic b-waves after UPARANT can be attributed to partially recovered post-receptor signalling in the cone-mediated pathway that is established when most of the rods are found to degenerate. 45 While ineffective on rods, UPARANT exerts neuroprotective effects on cones as demonstrated here by the increased amplitude of cone photopic b-waves and also supported by a significant preservation in cone arrestin loss and a substantial rescue of cones in the entire retina thus indicating that UPARANT differentially interferes with mechanisms underlying rod or cone death. As rods degenerate for a genetic defect and cones die more slowly due to inflammation, it is conceivable that UPARANT may have no effect on rod degeneration while mainly counteracting inflammatory-driven cone death.…”

“…This is supported by the kinetic analysis of rod‐mediated a‐waves further indicating that UPARANT does not affect rod neurodegeneration as also confirmed by the lack of rod preservation using Western blot analysis of rod photoreceptor markers. On the other hand, improvement of scotopic b‐waves after UPARANT can be attributed to partially recovered post‐receptor signalling in the cone‐mediated pathway that is established when most of the rods are found to degenerate . While ineffective on rods, UPARANT exerts neuroprotective effects on cones as demonstrated here by the increased amplitude of cone photopic b‐waves and also supported by a significant preservation in cone arrestin loss and a substantial rescue of cones in the entire retina thus indicating that UPARANT differentially interferes with mechanisms underlying rod or cone death.…”

Analytical methods for assessing retinal cell coupling using cut-loading

“…The most common technique for analysing cut-loaded tissues is to use the space constant from an exponential decay function fitted to the fluorescent intensity of the tissue measured per unit distance from the cut location [ 32 , 34 , 35 ]. This technique has several limitations in that: 1) it does not account for variation in cell density between tissues or sampling location, 2) the equation is fitted to data describing the mean fluorescence of an area containing both cells and non-specific background fluorescence, 3) the technique is limited to studying cell populations isolated in a particular layer of the retina e.g., photoreceptors or horizontal cells and 4) space constant values obtained via this method cannot be directly compared to those obtained via other techniques.…”